Versatile Synthesis of 5-Aminoimidazole-4-carboxylic Acid Derivatives

Abstract

5-Amino imidazole 4-substituted carboxamidines and 4-substituted imidoyl cyanides were selectively obtained under mild experimental conditions from reaction of the easily accessible 5-amino-4-cyanoformimidoyl imidazoles with primary aliphatic and aromatic amines, ammonia, and amino acids in a one-pot reaction. When alcohols were used, the corresponding 5-aminoimidazole 4-carboximidates were isolated. An equally simple reaction occurred when the starting imidazoles were combined with water to give 5-aminoimidazole 4-acyl cyanides.

Key words

heterocycles - imidazole - carboxamidine - carboximidate - imidoyl cyanides

References and Notes

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12

General Procedure for the Synthesis of 1˙TFA Salts
TFA (1.0 equiv) was added to a suspension of imidazole 1 (1.0-2.0 mmol) in CH₂Cl₂ or MeCN (3.0-5.0 mL) at r.t. leading to a homogeneous solution. After 1 min, a yellow solid precipitated from solution and was filtered and washed with Et₂O to give compound 1˙TFA (76-88%).
[5-Amino-1-(2-hydroxyethyl)-1 H -imidazol-4-yl] (Cyano)methaniminium 2,2,2-Trifluoroacetate (1a˙TFA)
Mp >110 ˚C (dec.). ^¹H NMR (300 MHz, DMSO-d ₆): δ = 10.21 (br s, 1 H), 8.79 (br s, 2 H), 7.91 (s, 1 H), 7.32 (t, J = 50 Hz, 0.2 H), 5.20 (s, 1 H), 4.11 (t, J = 4.7 Hz, 2 H), 3.83 (t, J = 4.7 Hz, 2 H). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 158.08 (q, J = 32 Hz), 152.62, 141.68, 131.83, 118.58, 116.44 (q, J = 300 Hz), 112.51, 57.74, 45.59. Anal. Calcd for C₉H₈F₃N₅O₃˙H₂O: C, 36.9; H, 3.0; F, 23.9; N, 19.90. Found: C, 36.9; H, 3.4; F, 23.6; N, 20.2. IR (mull): 3422, 3092, 3059, 1690 (CO), 1663, 1576 cm^-¹.

13

General Procedure for the Synthesis of 3b×TFA
Method B TFA (1 equiv) was added to a suspension of imidazole 1b (1.7 mmol) in EtOH (3 mL), and the mixture was stirred for 1 d at r.t. The solid was filtered and washed with EtOH and Et₂O (3b×TFA, 69%).
[5-Amino-1-(4-methoxyphenyl)-1 H -imidazol-4-yl] (Ethoxy)methaniminium 2,2,2-Trifluoroacetate (3b˙TFA)
Mp 241-242 ˚C. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 9.94 (br s, 1 H), 9.57 (br s, 1 H), 7.58 (s, 1 H), 7.40 (d, J = 9.0 Hz, 2 H), 7.13 (d, J = 8.7 Hz, 2 H), 6.61 (s, 2 H), 4.52 (q, J = 6.9 Hz, 2 H), 3.82 (s, 3 H), 1.30 (t, J = 6.9 Hz, 3 H). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 165.64, 159.88, 157.94 (q, J = 31 Hz), 148.05, 135.50, 127.73, 125.69, 117.94 (q, J = 299 Hz), 115.22, 105.10, 67.36, 55.66, 13.96. Anal. Calcd for C₁₅H₁₇N₄O₄: C, 48.13; H, 4.58; N, 14.97. Found: C, 48.55; H, 4.44; N, 15.23. IR (mull): 3471, 3108, 2700, 1673, 1634, 1513 cm^-¹.

14

Typical Procedure for the Synthesis of 4a
Method A A suspension of 1a˙TFA (2.4 mmol) in cold H₂O (4-5 mL) was stirred at 4 ˚C. After 13 d the solid was filtered and washed with cold H₂O to give 4a (60%).
5-Amino-1-(2-hydroxyethyl)-1 H -imidazole-4-carbonyl Cyanide 4a
Mp >196 ˚C (dec.). ^¹H NMR (300 MHz, DMSO-d ₆): δ = 7.71 (br s, 2 H), 7.42 (s, 1 H), 5.15 (br s, 1 H), 4.02 (t, J = 4.8 Hz, 2 H), 3.73 (t, J = 4.8 Hz, 2 H). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 155.49, 151.48, 137.58, 121.29, 115.68, 59.37, 46.09. Anal. Calcd for C₇H₈N₄O₂: C, 46.67; H, 4.48; N, 31.10. Found: C, 46.70; H, 4.31; N, 30.82. IR (mull): 3409, 3316, 3235, 3160, 3125, 2221, 1642, 1613, 1563, 1527 cm^-¹.

15

Typical Procedure for the Synthesis of Amidines 5
Method B
TFA (1.0 equiv) was added to a suspension of 1b (1.36 mmol) in MeCN (4.0 mL). The mixture was stirred at r.t. leading to a yellow precipitate. Addition of benzylamine resulted in a white solid. The mixture was stirred at r.t. for 1 d. The solid was filtered and washed with MeCN and Et₂O to give 5b˙TFA (84%). A solution of aq Na₂CO₃ (1.4 mL, 2 equiv) was added to a suspension of 5b˙TFA (0.34 mmol) in EtOH (0.5 mL) at r.t., under magnetic stirring. After 5 min, the solution was kept in an ice bath for 1 h. The precipitate was filtered and washed with ice water (93%).
Method D AcOH (1 equiv) was added to a suspension of imidazole 1f (2.70 mmol) in MeCN (2 mL) followed by addition of benzylamine. The mixture was stirred at ca. 40 ˚C for 20 min. After 10 min at 0 ˚C, the solid was filtered and washed with cold MeCN and cold Et₂O to give 5f˙AcOH (76%).
Method E A catalytic amount of AcOH was added to a suspension of imidazole 1f (1.52 mmol) in MeCN (2 mL) followed by addition of benzylamine (1.2 equiv). The mixture was stirred at ca. 40 ˚C for 9 h followed by 10 min at 0 ˚C. After addition of EtOH (1 mL) the solid was filtered and washed with cold MeCN and ice-cold Et₂O to give 5f˙AcOH (63%).
5-Amino- N -benzyl-1-(4-methoxyphenyl)-1 H -imidazole-4-carboximidamide 2,2,2-Trifluoroacetate (5b˙TFA) Mp 163-164 ˚C. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 9.00 (br s, 1 H), 8.27 (br s, 1 H), 7.59 (s, 1 H), 7.42-7.36 (m, 6 H), 7.30 (m, 1 H), 7.13 (d, J = 8.7 Hz, 2 H), 6.31 (br s, 2 H), 4.67 (s, 2 H), 3.83 (s, 3 H). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 159.78, 157.91 (q, J = 30.5 Hz), 155.94, 143.11, 136.95, 133.77, 128.53, 127.90, 127.40, 127.12, 125.92, 117.35 (q, J = 299.0 Hz), 115.12, 106.92, 55.60, 44.10. Anal. Calcd for C₂₀H₂₀F₃N₅O₃: C, 55.17; H, 4.63; N, 16.08. Found: C, 55.27; H, 4.75; N, 16.04. IR (mull): 3394, 3311, 3203, 1676, 1645 (CO), 1616 cm^-¹. 5-Amino- N -benzyl-1-(4-methoxyphenyl)-1 H -imidazole-4-carboximidamide (5b)
Mp 157-158 ˚C. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 7.40 (d, J = 9.0 Hz, 2 H), 7.37 (d, J = 6.9 Hz, 2 H), 7.30 (t, J = 7.8 Hz, 2 H), 7.26 (s, 1 H), 7.19 (t, J = 7.2 Hz, 1 H), 7.08 (d, J = 9.0 Hz, 2 H), 6.02 (br s, 2 H), 5.90 (br s, 2 H), 4.32 (s, 2 H), 3.80 (s, 3 H). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 158.76, 154.60 (br), 142.31 (br), 139.55, 128.64, 128.12, 127.85, 127.30, 126.07, 125.99, 114.85, 114.20, 55.51, 49.11 (br). Anal. Calcd for C₁₈H₁₉N₅O: C, 67.27; H, 5.96; N, 21.79. Found: C, 67.35; H, 5.83; N, 21.57. IR (mull): 3495, 3390, 3321, 3262, 3117, 1623, 1588, 1517 cm^-¹.

16

Typical Procedure for the Synthesis of 6b
TFA (1 equiv) was added to a suspension of 1b (1.4 mmol) at 30 ˚C. Benzylamine was added, and the solution was stirred at r.t. for 18 h. The product was filtered and washed with EtOH, MeCN, and Et₂O (6b, 58%).
5-Amino- N -benzyl-1-(4-methoxyphenyl)-1 H -imidazole-4-carbimidoyl Cyanide (6b)
Mp 163-165 ˚C. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 7.39 (s, 1 H), 7.41 (dt, J = 9.6, 2.1 Hz, 2 H), 7.36-7.34 (m, 4 H), 7.26-7.25 (m, 1 H), 7.10 (dt, J = 9.3, 2.1 Hz, 2 H), 6.45 (br s, 2 H), 4.95 (s, 2 H), 3.81 (s, 3 H). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 159.34, 143.43, 139.34, 138.11, 132.17, 128.59, 127.63, 127.08, 126.64, 126.49, 115.78, 115.04, 110.02, 59.84, 55.57. Anal. Calcd for C₁₉H₁₇N₅O: C, 68.87; H, 5.17; N, 21.13. Found: C, 68.87; H, 5.03; N, 21.14. IR (mull): 3307, 3184, 3127, 3065, 3029, 1614, 1580, 1539, 1518 cm^-¹.

17

CCDC 825265 and 825266 contain the supplementary crystallographic data for this paper (compounds 5i˙AcOH and 5m, respectively). These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [e-mail], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: [phone].